Mitochondria controls nucleus during metabolic stress

Research for the first time show that the mitochondrial and nuclear genomes co-evolved to independently cross-regulate each other. The findings are significant because aging causes cells to break down, leading to diseases such as cancer and Alzheimer's. The study appears today in the journal Cell Metabolism.

"Mitochondria have their own DNA that presumably comes from ancient bacteria that joined our cells a long time ago. We didn't know that our mitochondrial DNA encoded messages to control the nucleus. In fact, the nucleus has been long thought to hold all our genetic blueprint for building and operating a cell," the senior author said. "This is a fundamental discovery that integrates our two genomes as a co-evolved genetic system and may have a lasting impact for a broad range of scientific and medical fields."

The researchers focused on the two parts of the cell that carry DNA: the nucleus and the mitochondria. Most genetic material resides in the nucleus, which is the largest component of the cell. Its DNA sends coded templates telling the cell what to do. Smaller mitochondria function as energy-producing factories, turning food into fuel to power the cell. But size can be misleading. The mitochondria also contain DNA, all of it inherited from the mother, and as the new study shows, they are not just taking orders from the nucleus.

Working with human cells, the scientists discovered that when a cell is under stress and starved for nutrients, MOTS-c, a small peptide encoded in the mitochondria DNA, moves into the nucleus to control genes and turn on a defensive system, including an antioxidant response.

More specifically I n the nucleus, MOTS-c regulated a broad range of genes in response to glucose restriction, including those with antioxidant response elements (ARE), and interacted with ARE-regulating stress-responsive transcription factors, such as nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2).

"Most diseases are due to aging, and aging leads to a breakdown in cell functions," the senior author said. "When things go wrong in the body, it's because some mechanism in the body went wrong. So, understanding how cells age means we have more insight into how the damage occurs and how we can prevent or fix it," the author added.